The transplantation of healthy organs from one person to replace diseased organs in another, referred to as an allograft, has been investigated for at least a hundred years. Modern transplantation had its beginnings more than 50 years ago when it was demonstrated that allograft rejection is an immunologic event. This illustrated that successful organ transplantation would depend on attenuating or otherwise altering the immune response to the allograft.
The feasibility of solid organ transplantation was first proven with the kidney, and the seminal work in renal transplantation established the foundation necessary to proceed with all other types of solid organ transplantations. Until 1967, the kidney was the only organ allograft to be successfully transplanted in humans. In July 1967, a child's hepatoma-riddled liver was replaced with a cadaveric donor liver. Under immunosuppression with the then novel combination of azathioprine, prednisone, and antilymphoid globulin, the child survived for more than a year before dying of metastases from the primary liver cancer. Using the same anti-rejection therapy, the first successful transplantations of the human heart, lung, and pancreas were soon performed.
First Successful Transplantation of Human Allografts(i.e., patient survival > 6 months)Organ(s)CityDateKidneyBoston1/24/59Bone marrowParis4/23/63LiverDenver7/23/67HeartCape Town1/2/68LungGhent11/14/68PancreasMinneapolis6/3/69Heart-LungPalo Alto3/9/81Multiabdominal visceraPittsburgh11/1/87Small bowel segmentCologne8/9/88Liver and intestineLondon, Ontario11/13/88Total small bowelParis3/18/89Pancreatic isletPittsburgh1/11/90
The emergence of transplantation has paralleled the development of increasingly potent immunosuppressive agents, progressively better methods of tissue and organ preservation, refinements in tissue typing and matching, and numerous innovations in surgical techniques. These accomplishments, in combination with sweeping advances in the general care of patients (e.g., antibiotics, anesthesia, blood banking, artificial kidney and heart-lung machines), ultimately made it possible to successfully engraft all of the vital vascular organs.
In 1977, cyclosporine was shown to be immunosuppressive, and it was first used in human trials for organ transplantation in 1978. Cyclosporine was found to selectively suppress the transplant recipient's immune system, allowing the patient to tolerate the grafted organ but still thwart routine infections. FDA approval of cyclosporine in 1983 thus revolutionized organ transplantation, with greatly improved chances for long-term survival of the patient and the transplanted organ.
Longest Living Adult RecipientsOrganDatePatient AgeYrs of FunctionKidney (LRD)1/31/633834 yrs, 11 moKidney (CAD)1/25/653832 yrs, 11 moPancreas12/3/802517 yrsLiver1/22/70327 yrs, 11 moHeart4/4/752822 yrs, 8 moHeart-Lung11/5/824015 yrs, 1 moLung (Single)9/6/88599 yrs, 4 moLung (Double)7/26/872510 yrs, 5 mo
Annually, nearly 50,000 new patients worldwide receive transplanted organs, and more than 200,000 transplant recipients in North America and Europe depend on daily cyclosporine therapy to prevent organ rejection.
Recent data indicate that, in the US, a new name is added to the United Network for Organ Sharing (UNOS) waiting list approximately every 15 minutes. Nearly 50,000 transplant procedures are performed each year throughout the world, and approximately 20,000 of these are performed in the US.
Number of Transplants Performed in the US in 1999Type of TransplantNumberKidney (4,153 were living donors)12,483Liver transplants4,698Pancreas alone transplants363Kidney-pancreas transplants946Intestine transplants70Heart transplants2,185Heart-lung transplants49Lung transplants885Total21,692
The current organ demand significantly exceeds the supply, as evidenced by the 40,000-plus individuals who remain untransplanted each year. In 1997 alone, 4,487 individuals in the US died while waiting for an organ. On Sep. 30, 2000, there were 72,070 individuals in the US awaiting transplantation. In an effort to increase the pool of suitable organs, researchers are experimenting with novel alternative measures such as xeno-transplantation (i.e., transplants from animals). In clinical settings, transplant surgeons are cutting adult livers in half and sewing them into children. Within three months, “cut-down” livers usually regenerate and adjust to the recipient's body. This trend is likely to continue until the shortage of organs is reversed.
Transplant Rejection
Despite chronic immunosuppressive therapy with cyclosporine and other drugs, approximately 30 percent of transplant patients experience one or more rejection episodes in the first year after surgery. These acute rejection episodes occur when T-cells recognize as foreign matter the HLA molecules on the donated organ tissue, which activates the T-cells. Once activated, these T-cells can attack and kill the foreign cells. Reversing the rejection requires a short course of powerful immunosuppressive medication, such as intensive steroid therapy. If that fails (which it does about half the time), anti-T-cell antibodies are administered. These biological agents typically are administered for 10 to 14 days, and work by binding to and destroying the patient's T-cells, thereby halting the acute rejection episode.
The first year after transplantation, the graft failure rate for kidney transplant patients is approximately 9 percent for patients whose transplant was received from a living donor, and about 19 percent for those whose transplant was cadaveric. The graft failure rate is higher for other types of organs. For kidney recipients, surgery to remove the failed organ, a return to dialysis and a possible second transplant are indicated. Failure to reverse the rejection of other transplanted organs, such as the liver or heart, often results in the death of the patient. The overall chance of surviving a liver transplant is 60–75% for adult patients and 80–90% for children.
The risk of rejection continues for the rest of the patient's life at 5 percent to 10 percent per year. At the end of 10 years, only an estimated 50 percent of organ recipients still have a functioning transplant.
Allograft rejection and its differentiation from other causes of organ dysfunction remain a diagnostic problem in transplant patients. Currently, acute rejection can be prevented by a combination of diagnostic and therapeutic modalities. Early detection requires frequent lab tests (e.g., measurement of bilirubin in the blood) and/or biopsies of the transplanted tissue.
What is needed are means and methods for detecting, preventing, and treating allograft rejection which do not have the side effects and other drawbacks of means and methods currently available.